Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/72—Nitrogen atoms
  • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
  • C07C271/06—Esters of carbamic acids
  • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
  • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
  • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
  • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
  • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D261/14—Nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D277/38—Nitrogen atoms
  • C07D277/44—Acylated amino or imino radicals
  • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof

Definitions

• This invention relates to a process for the synthesis of 1,2-benzothiazine-3-carboxamides, and in particular to the preparation of N-aryl-3,4-dihydro-2-alkyl-4-oxo- 2I-I- l ,2-benzothiazine-3-carboxamide l,l-dioxides, a class of compounds useful as antiinflammatory agents, and to N-aryl-N'-alkyl-N-(2'-alkoxycarbonylbenzenesulfonyl)glycineamides as useful intermediates for said process.
• R is selected from the group consisting of pheny; monosubstituted phenyl wherein said substituent is fluoro, chloro, methyl or methoxy; 'Z-thiazolyl; 4,5-dimethyl-2-thiazolyl; 2-pyridyl; 6-methyl-2-pyridyl; and -methyl-3-isoxazolyl; R is alkyl containing one to three carbon atoms; and X is a substituent selected from the group consisting of hydrogen, methyl, methoxy, fluoro, chloro and bromo, which comprises contacting a compound of the formula:
• COzRa son lcmooNnm wherein R is alkyl containing from l to 3 carbon atoms, with an alkali or alkaline earth metal hydride in a reaction-inert solvent at 50-l50 C. leads to the desired compounds which are potent nonsteroidal antiinflammatory agents.
• R is selected from the group consisting of phenyl; monosubstituted phenyl wherein said substituent is fluoro, chloro, methyl or'methoxy; 2-thiazolyl; 4,5-dimethyl-2-thiazolyl; Z-pyridyl; 6-methyl-2-pyridyl; and 5-methyl-3-isoxazolyl; R is alkyl containing one to three carbon atoms; and X is a substituent selected from the group consisting of hydrogen, methyl, methoxy, fluoro, chloro and bromo.
• R is alkyl of up to 8 carbon atoms, aryl or aralkyl, and wherein the metal hydride is replaced by a suitable organometallic reagent.
• a preferred feature of the process leading to the compounds of the present invention is the use of sodium hydride as the metal hydride and tetrahydrofuran as the reaction-inert solvent, while the preferred intermediates are N-(aryl)-N-methyl-N-(2- alkoxycarbonylbenzenesulfonyl)glycineamides.
• reaction-inert solvent By such a solvent, or mixtures thereof, is contemplated those, which under the conditions of the instant process, do not enter into appreciable reaction with either the starting reagents or products. It is preferred that non-aqueous, aprotic, polar atures of 50100 C. are employed, the reaction time will vary between 4-10 hours.
• temperature range it is preferred, for practical reasons, that the instantly claimed process be heated in order to obtain optimum yields of the desired products.
• a temperature range of 50-150 C. is operative, with a preferred range of 50-l00 C.
• the mixture is cooled and added to water, to which is then added sufficient acid to render the mixture acidic to litmus paper.
• the product is then extracted with a waterimmiscible solvent, such as methylene chloride or chloroform, and the organic extracts concentrated to dryness. Further purification of the product is effected by recrystallization from an appropriate solvent.
• the compounds ofthe present process invention are useful as antiinflammatory agents, and U.S. Pat. No. 3,591,584 teaches how to use these compounds for this utility.
• Of particular interest in the present invention are the synthesis of benzothiazine 1,1-dioxide wherein R is methyl, X is hydrogen and R is phenyl, Z-pyridyl, 2-thiazolyl or 6-methyl2- pyridyl.
• the particularly preferred benzenesulfonylglycineamide intermediates are those wherein R is phenyl, pyridyl, Z-thiazolyl or 6-methy1-2-pyridyl and R and R are each methyl.
• the prod-' uct is extracted with chloroform and the extracts combined and dried over sodium sulfate.
• the drying agent is filtered and the filtrate concentrated to a gum, which on trituration with 0.5 m]. of chloroform and 3 ml. of hexane yields 3.3 mg. of the desired product, m.p. l72l93 C. Recrystallization, m.p. 256 C. dec, provides material identical to that prepared in U.S. Pat. No. 3,591,584.
• EXAMPLE 2 3 ,4-Dihydro-2-methyl-4-oxo-2H-1 ,Z-benzothiazine carboxanilide 1,1-dioxide
• the product is extracted with chloroform and the combined chloroform extracts (3) are back-washed with water and dried over sodium sulfate.
• the solvent is removed under reduced pressure and the residue gum induced to crystallize by trituration with cold isopropanol.
• the filtered product proves to be identical with that reported in U.S. Pat. No. 3,591,584.
• the cooled reaction mixture is quenched in ice, acidified, and the product extracted with methylene chloride.
• the organic extracts are combined, dried over sodium sulfate and concentrated in vacuo to a gum. Trituration with cold acetonitrile followed by filtration provides the desired product.
• EXAMPLE 4 3 -Chloro3 ,4-dihydro-2-rnethyl 4-oxo-2H -1 ,2 benzothiazine-3-carboxanilide 1,1-dioxide
• the procedure of Example 1 is repeated, starting with 4.11 g. (0.01 mole) of N-(3-chloropheny1)-N- methyl-N-(2-methoxycarbonylbenzenesulfonyl)- glycineamide and 800 mg. (0.02 mole) of a 50 percent suspension of potassium hydride in 40 ml. of dimethylsulfoxide. to yield the desired crude product. Further purification is achieved by recrystallization from acetic acid.
• the resulting reaction mixture is allowed to stir at room temperature for l hr. and is then heated under reflux for 2 hrs.
• the solution is cooled in ice and the resulting solids filtered and dried, 4.6 g., m.p. 203205 C.
• the analytical sample is recrystallized from ethanoldiethyl ether.
• the free base is generated by treatment of an aqueous solution of the hydrobromide salt with an aqueous sodium hydroxide solution, followed by extraction of the free base into a water-immiscible solvent such as benzene.
• PR EPARATlON C Z-Carboalkoxybenzenesulfonyl Chlorides 1 A heavy precipitate resulting from the addition of 85 ml. of l2N hydrochloric acid to 37.8 g. of methyl anthranilate in 50 ml. of cold water is stirred and maintained at 0-5 C. in an ice bath while 19.0 g. of sodium nitrite in ml. of cold water is added dropwise. The resulting pale yellow soltuion is stirred for 30 min. at 0-5 C. and is filtered through a sentered glass filter.
• the above filtrate containing the diazonium salt is slowly added dropwise to a solution resulting from the addition of a cold solution of g. of sulfur dioxide in 200 ml. of glacial acetic acid to a cold suspension of 8 65 g. of cupric chloride in 11 1 ml. of glacial acetic acid.
• N-Benzenesulfonylglycineamides 1. N-(2-Thiazolyl)-N'-methyl-N-(2' methoxycarbonylbenzenesulfonyl)glycineamide N-Methyl-N-(Z-thiazolyl)glycinemide, generated from 4.84 g. of the corresponding dihydrobromide salt, in 50 ml. of benzene is treated with 3.41 g. of 2- methoxycarbonylbenzenesulfonyl chloride, and the resulting mixture heated under reflux for 30 hrs. The reaction mixture is cooled and the precipitated solids filtered, washed with benzene and partitioned between water and chloroform.
• the water layer is extracted several additional times with chloroform, and the chloroform extracts combined and dried over sodium sulfate.
• the organic solvent is removed in vacuo and the tan residual solid is triturated with hexane and filtered, 640 mg, mp 215 C. dec.
• the analytical sample is recrystallized from methanol, mp. 216-2l8 C. dec.
• metal hydrides utilized in the present'process are either commercially available or are prepared by literature procedures, Moeller, Inorganic Chemistry," John Wiley Sons, New York, New York 1958.
• X is a substituent selectedfrom the group consisting of hydrogen, methyl, methoxy, fluoro, chlo ro and bromo, which comprises contacting a compound of the formula:
• R is alkyl containing from 1 to 3 carbon atoms, with a metal hydride selected from the group consisting of alkali and alkaline earth metal hydrides, in a reaction-inert solvent at 50-l50 C 2.
• a metal hydride selected from the group consisting of alkali and alkaline earth metal hydrides, in a reaction-inert solvent at 50-l50 C 2.
• the metal hydride is sodium hydride.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Plural Heterocyclic Compounds (AREA)
• Nitrogen- Or Sulfur-Containing Heterocyclic Ring Compounds With Rings Of Six Or More Members (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Thiazole And Isothizaole Compounds (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

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• 1973
  • 1973-04-23 US US00353607A patent/US3853862A/en not_active Expired - Lifetime
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• 1974
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• 1977
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